Three types of opioid receptors, i.e., μ, δ, and κ receptors, are known, and morphine having potent affinity to μ receptor has been used as an analgesic for a long time. Although morphine has potent analgesic effect, it is known that morphine causes adverse events such as formation of dependence, respiratory depression, and constipation via μ receptor. It is also known that δ receptor agonists are not involved in the adverse events observed for morphine, although δ receptor also participates in the analgesic effect. Therefore, it is considered that a δ receptor-selective agonist may have a potential as an analgesic superior to morphine, and for this reason, researches focusing on the discovery of such analgesic have been actively conducted. However, any δ receptor agonist has not yet been approved as a therapeutic or prophylactic agent.
Patent document 1 describes that a compound represented by the following formula (A):
has an opioid δ receptor agonistic activity. Further, in Non-patent document 1, the inventors of the present invention made reports concerning a compound represented by the following formula (B):
however, this compound has higher affinity to μ receptor than δ receptors.
Further, by comparison of the compound represented by the aforementioned formula (B) and the morphinan derivatives represented by the general formula (I) mentioned below, it is noted that there is difference in chemical structure, i.e., the components of the rings of the two compounds are significantly different. More specifically, in the compound represented by the aforementioned formula (B), the five membered ring moiety containing nitrogen has an amide structure, and one of the carbon atoms binding to the nitrogen atom is further substituted with hydroxy group (hemiaminal structure is formed). Whilst, in the morphinan derivatives of the present invention represented by the general formula (I) mentioned below, the corresponding five membered ring moiety has an amine structure (i.e., not having carbonyl group), and moreover, this five membered ring moiety does not have hydroxy group.
The inventors of the present invention recently filed a patent application for compounds corresponding to the compound represented by the aforementioned formula (B) in which two of the hydroxy groups at the 4- and 6-positions are bound via a methylene chain (Patent document 2, Non-patent document 2). However, the morphinan derivatives represented by the general formula (I) mentioned below do not have any bond between the 4- and 6-positions.